Human papillomaviruses (HPVs) are small DNA viruses that infect various epithelial tissues including the epidermis and epithelial linings of the upper respiratory system and anogenital tract. A subset of anogenital HPVs, the 'high risk' HPVs including HPV-16 and 18 genotypes, are associated with greater than 95% of cervical carcinomas. Two genes of the high-risk anogenital human papillomaviruses (HPV), E6 and E7, are implicated in cervical carcinogenesis owing to their selective and continued expression in those cancers. E6 and E7 proteins possess multiple biochemical activities including but not limited to their capacities to inactivate tumor suppressor genes p53 and pRB, respectively. We and others have demonstrated that the inactivation of p53 and pRB cannot account completely for E6 and E7's transforming potential in tissue culture and tumorigenic properties in animal models. The goals of this application are to identify the cellular targets of E6 and E7 that contribute to their oncogenic function. We shall use transgenic mouse models in which the E6 and E7 genes of the high risk HPV most commonly associated with human cervical cancer, HPV-16, are directed in their expression to stratified squamous epithelia. These mouse models permit us to evaluate acute and long-term effects of E6 and E7 expression on mouse tissue including tumorigenesis in the epidermis and cervix. The availability of mouse strains that have been altered in specific cellular genes provide us a compelling approach to defining the cellular targets of E6 and E7 that contribute to HPV-associated cancer.